Tension trapping of carbonyl ylides facilitated by a change in polymer backbone

Epoxidized polybutadiene and epoxidized polynorbornene were subjected to pulsed ultrasound in the presence of small molecules capable of being trapped by carbonyl ylides. When epoxidized polybutadiene was sonicated, there was no observable small molecule addition to the polymer. Concurrently, no appreciable isomerization (cis to trans epoxide) was observed, indicating that the epoxide rings along the backbone are not mechanically active under the experimental conditions employed. In contrast, when epoxidized polynorbornene was subjected to the same conditions, both addition of ylide trapping reagents and net isomerization of cis to trans epoxide were observed. The results demonstrate the mechanical activity of epoxides, show that mechanophore activity is determined not only by the functional group but also the polymer backbone in which it is embedded, and facilitate a characterization of the reactivity of the ring-opened dialkyl epoxide.     

Modeling of solvent flow effects in enzyme catalysis under physiological conditions

A stochastic model for the dynamics of enzymatic catalysis in explicit, effective solvents under physiological conditions is presented. Analytically-computed first passage time densities of a diffusing particle in a spherical shell with absorbing boundaries are combined with densities obtained from explicit simulation to obtain the overall probability density for the total reaction cycle time of the enzymatic system. The method is used to investigate the catalytic transfer of a phosphoryl group in a phosphoglycerate kinase-ADP-bis phosphoglycerate system, one of the steps of glycolysis. The direct simulation of the enzyme-substrate binding and reaction is carried out using an elastic network model for the protein, and the solvent motions are described by multiparticle collision dynamics which incorporates hydrodynamic flow effects. Systems where solvent-enzyme coupling occurs through explicit intermolecular interactions, as well as systems where this coupling is taken into account by including the protein and substrate in the multiparticle collision step, are investigated and compared with simulations where hydrodynamic coupling is absent. It is demonstrated that the flow of solvent particles around the enzyme facilitates the large-scale hinge motion of the enzyme with bound substrates, and has a significant impact on the shape of the probability densities and average time scales of substrate binding for substrates near the enzyme, the closure of the enzyme after binding, and the overall time of completion of the cycle.     

Dynamic combinatorial libraries for the recognition of heavy metal ions

We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr(2+) and Ba(2+) induce characteristic changes in the DCLs. Four macrocycles were isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by UV-Vis spectroscopy confirm the selectivity observed in the DCLs.     

Synthesis, characterization, and glutathionylation of cobalamin model complexes [Co(N4PyCO2Me)Cl]Cl2 and [Co(Bn-CDPy3)Cl]Cl2

Synthetic Co(III) complexes containing N5 donor sets undergo glutathionylation to generate biomimetic species of glutathionylcobalamin (GSCbl), an important form of cobalamin (Cbl) found in nature. For this study, a new Co(III) complex was synthesized derived from the polypyridyl pentadentate N5 ligand N4PyCO(2)Me (1). The compound [Co(N4PyCO(2)Me)Cl]Cl(2) (3) was characterized by X-ray crystallography, UV-vis, IR, (1)H NMR, and (13)C NMR spectroscopies and mass spectrometry (HRMS). Reaction of 3 with glutathione (GSH) in H(2)O generates the biomimetic species [Co(N4PyCO(2)Me)(SG)](2+) (5), which was generated in situ and characterized by UV-vis and (1)H NMR spectroscopies and HRMS. (1)H NMR and UV-vis spectroscopic data are consistent with ligation of the cysteine thiolate of GSH to the Co(III) center of 5, as occurs in GSCbl. Kinetic analysis indicated that the substitution of chloride by GS(-) occurs by a second-order process [k(1) = (10.1 ± 0.7) × 10(-2) M(-1) s(-1)]. The observed equilibrium constant for formation of 5 (K(obs) = 870 ± 50 M(-1)) is about 3 orders of magnitude smaller than for GSCbl. Reaction of the Co(III) complex [Co(Bn-CDPy3)Cl]Cl(2) (4) with GSH generates glutathionylated species [Co(Bn-CDPy3)(GS)](2+) (6), analogous to 5. Glutathionylation of 4 occurs at a similar rate [k(2) = (8.4 ± 0.5) × 10(-2) M(-1) s(-1)], and the observed equilibrium constant (K(obs) = 740 ± 47 M(-1)) is slightly smaller than for 5. Glutathionylation showed a significant pH dependence, where rates increased with pH. Taken together, these results suggest that glutathionylation is a general reaction for Co(III) complexes related to Cbl.     

VinaMPI: Facilitating multiple receptor high‐throughput virtual docking on high‐performance computers

The program VinaMPI has been developed to enable massively large virtual drug screens on leadership‐class computing resources, using a large number of cores to decrease the time‐to‐completion of the screen. VinaMPI is a massively parallel Message Passing Interface (MPI) program based on the multithreaded virtual docking program AutodockVina, and is used to distribute tasks while multithreading is used to speed‐up individual docking tasks. VinaMPI uses a distribution scheme in which tasks are evenly distributed to the workers based on the complexity of each task, as defined by the number of rotatable bonds in each chemical compound investigated. VinaMPI efficiently handles multiple proteins in a ligand screen, allowing for high‐throughput inverse docking that presents new opportunities for improving the efficiency of the drug discovery pipeline. VinaMPI successfully ran on 84,672 cores with a continual decrease in job completion time with increasing core count. The ratio of the number of tasks in a screening to the number of workers should be at least around 100 in order to have a good load balance and an optimal job completion time. The code is freely available and downloadable. Instructions for downloading and using the code are provided in the Supporting Information. © 2013 Wiley Periodicals, Inc.     

Ritter Reactions between Alcohols and Acetonitrile Mediated by the Conducting Polymer Poly-(3,4-ethylenedioxy Thiophene) (PEDOT)

Herein, we report new reactivity of the conducting polymer, poly-(3,4-ethylenedioxy thiophene) (PEDOT), where PEDOT mediates a Ritter reaction between alcohols and acetonitrile. The yields were variable and in most cases competitive with results obtained using sulfuric acid. Attempts at a stoichiometric reaction between benzonitrile and diphenylmethanol are also reported herein. Finally, described here are preliminary mechanistic studies that suggest PEDOT is behaving as an alcohol-selective or specific Lewis acid.

Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for full experimental and spectral details.     

Selective Preparation of 4-(Bromo or Iodo)-2,5-dimethoxybenzonitrile and 2-(Bromo or Iodo)-3,6-dimethoxybenzonitrile from 2,5-Dimethoxybenzaldehyde

By use of appropriate reactions and sequence of steps, 2,5-dimethoxybenzaldehyde can be converted either to 4-(bromo or iodo)-2,5-dimethoxybenzonitrile or 2-(bromo or iodo)-3,6-dimethoxybenzonitrile.